Bardoxolone-Methyl (CDDO-Me) impairs tumor growth and radioresistance of oral squamous cell carcinoma (OSCC) cells via accumulation of reactive oxygen species

Abstract

Radiotherapy (RT) represents a common treatment strategy for patients suffering from oral squamous cell carcinoma (OSCC). However, application of RT is immanently limited by radio-sensitivity of normal tissue surrounding the tumor sites. In this study, we used normal human epithelial keratinocytes (NHEK) and OSCC cells (Cal-27) as models to investigate radio-modulating and anti-tumor effects of the synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9,-dien-28-oic acid methyl ester (CDDO-Me). Nanomolar CDDO-Me significantly enhanced antioxidative heme oxygenase-1 (HO-1) levels in NHEK only and not in the OSCC cell line, as shown by immunoblotting. In the presence of CDDO-Me reactive oxygen species (ROS) were found to be reduced in NHEK when applying radiation doses of 8 Gy, whereas ROS levels in OSCC cells rose significantly even without radiation. In parallel, CDDO-Me was shown to enhance metabolic activity in malignant cells only as indicated by significant accumulation of reducing equivalents NADPH/NADH. Clonogenic survival was left unchanged by CDDO-Me treatment in NHEK but revealed to be abolished almost completely in OSCC cells. The latter effect was confirmed by a CDDO-Me induced significant reduction of OSCC tumor xenograft-growth in-ovo applying the chick chorioallantoic membrane (CAM) assay. Our results strongly indicate anti-cancer and radio-sensitizing effects of CDDO-Me treatment in OSCC cells, whereas nanomolar CDDO-Me failed to provoke clear detrimental consequences in non-malignant keratinocytes. We conclude, that the observed differential aftermath of CDDO-Me treatment in malignant OSCC and non-malignant skin cells may be capitalized to broaden the therapeutic range of clinical RT.